DESCRIPTION (Adapted from applicant's description) Circadian pacemakers are self-sustaining oscillators that free-run with a stable period under constant conditions. Under normal conditions, the period and phase of circadian pacemakers are established by environmental stimuli, particularly the solar light-dark cycle. Many common sleep disorders are thought to result from disturbance of this rhythm. Work in organisms such as neurospora, arabidopsis, and drosophila have begun to elucidate molecular mechanisms underlying this phenomenon of inherent periodicity and entrainment to environmental cues. This has been possible, in part, through recognition of monogenic circadian rhythm disorders in drosophila, mapping and cloning of the responsible genes, and molecular characterization of the proteins encoded by these genes. A similar approach is now being applied to rodents where single-gene disorders of circadian rhythms have now been recognized. To date, this approach has not been possible in humans. Genetic factors in human sleep disorders are well recognized but monogenic circadian dysrythmias have not been described. We have identified two large families with an autosomal dominant, highly penetrant circadian rhythm disturbance called advanced sleep phase syndrome (ASPS). In these families, the disorder occurs in the absence of other explicable cause (depression, narcolepsy, sleep apnea, etc.) and has onset in childhood or adolescence. Affected individuals have advance of their major sleep episode relative to the desired clock time, resulting in symptoms of compelling evening sleepiness, early sleep onset, and awakening that is earlier than desired. One family (K2174) is sufficiently large to map an ASPS locus with a LOD score approaching 6. Another large family and one isolated case are currently being collected. This proposal outlines a plan to characterize other overt rhythms in these families, and to use genetic approaches to localize and identify the ASPS-causing gene. Identification of a human circadian rhythm gene will be the first piece of the puzzle (much like per in drosophila) around which a picture of the molecular mechanism of human circadian rhythms may evolve. (end of description)